A number of epidemiological studies suggest that dietary selenium (Se) is inversely correlated with human carcinogenesis. Recently, a double blind study using moderate doses of Se has demonstrated a significant reduction in human cancer incidence at several sites, including lung, prostate and intestine. The exact cause of human cancer reduction by Se remains unclear. Phospholipid-hydroperoxide glutathione peroxidase (PHGPx) is a selenoenzyme that reduces hydroperoxides of phospholipids, which arise from oxidized phospholipids in biomembranes. Preliminary work also suggests that PHGPx has a role in repairing oxidative damage to DNA, since reduction of thymine hydroperoxide by PHGPx is about four orders of magnitude more efficient than by other selenium-dependent enzymes. In order to determine if PHGPx has a direct role in DNA repair and mutagenesis, the proposal describes the generation of PHGPx-/- cell lines and PHGPx-/- mice. These will be used to determine spontaneous mutation and induced mutagenesis both in vitro and in vivo. The long term objective of this study is to understand the basis for Se action in cancer chemoprevention.